R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylmethoxy)-2-(2,4-dichlorophenyl)ethyl]-1h-imidazole and its salts, method for preparing, composition possessing antifungal effect

FIELD: organic chemistry, chemical technology, medicine, veterinary science.

SUBSTANCE: invention describes the compound R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylmethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole of the formula (I) and its salts, in particular, its mononitrate. Also, invention relates to a method for preparing compound of the formula (I) possessing antifungal effect based on compound of the formula (I), and using compound of the formula (I) as an active component of the antifungal composition. Compound of the formula (I) can be used in compositions for treatment of fungal infections in humans or animals and against diseases of agricultural crops.

EFFECT: improved preparing method, valuable properties of compound and composition.

15 cl, 1 tbl, 10 ex

 

The technical field to which the invention relates.

The present invention relates to R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole(R-(-)-sertaconazole) and its salts, method of its production, to compositions which contain the above-mentioned connection, and to the use of these compositions for the treatment of fungal infections and diseases of agricultural crops.

The level of technology

Racemic 1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole is a known compound named sertaconazole (WHO, INN), which is used as an antifungal agent for the treatment of diseases caused by fungi and yeast in humans and animals. Obtaining the specified connection and its Mononitrate described in European patent No 151477.

Disclosure of inventions

The present invention relates to R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole of the formula I

and its pharmaceutically acceptable additive salts.

R-(-)-enantiomer of sertaconazole has activity against fungi and yeast, which is approximately 2 times higher compared to the racemic mixture, (because of its affinity to the target 2 times higher), as shown in table 1. These data suggest that the introduction of R-()-sertaconazole dose, part 1/2 dose of racemic sertaconazole, thus will reduce the risk of adverse action and will provide suppression of nonspecific toxicity associated with undesirable admixture of S-(+)-enantiomer.

Mononitrate is the preferred salt of R-(-)-sertaconazole.

The present invention relates also to a method for production of R-(-)-enantiomer of sertaconazole and its pharmaceutically acceptable salts, and the method includes the interaction of R-(-)-1-(2,4-dichlorophenyl)-2-imidazol-1-retinol formula ((R)-(-)-(III)

with 3-halogenmethyl-7-chlorobenzo[b]thiophene of formula IV

where X is halogen.

The connection can be isolated from the reaction mixture known in the field of ways. If necessary, the crude product can then be cleaned known in the field of ways, for example by crystallization and/or chromatography.

Obtain S-(+)-enantiomer of sertaconazole can be the appropriate method using S-(+)-1-(2,4-dichlorophenyl)-2-imidazol-1-retinol instead of R-(-)-enantiomer.

A necessary condition for obtaining enantiomers of sertaconazole the above-mentioned way is to obtain the corresponding enantiomers of intermediate derivative 1-(2,4-dichlorophenyl)-2-imidazol-1-retinol (III).

Two enantiomer-(2,4-dichlorophenyl)-2-imidazol-1-retinol (III) can be obtained by separation of the corresponding racemic mixture with an optically active acid, preferably L-tartaric acid, D-tartaric acid, Dibenzoyl-L-tartaric acid, Dibenzoyl-D-tartaric acid or the like, and using the method described in UK patent No 1244530 and article Lammerhofer M. and W. Lindner, Chiralitiy, 6:261-269,1994.(R)-(-)-1-(2,4-Dichlorophenyl)-2-imidazol-1-retinol also obtained by the method of enantioselective recovery 1-(2,4-dichlorophenyl)-2-imidazol-1-ratanana (II) using (-)-β-chlorodiisopinocampheylborane [(-)-DIP-chloride] with the formation of (R)-(-)-1-(2,4-dichlorophenyl)-2-imidazol-1-retinol ((R)-(-)-III) with acceptable optical purity.

The interaction of one enantiomer of the intermediate derivative of the formula (III) with 3-halogenmethyl-7-chlorobenzo[b]thiophene (IV) leads to the formation of the corresponding enantiomer of sertaconazole in the form of free base. As a 3-halogenmethyl-7-chlorobenzo[b]thiophene preferred are 3-chloromethyl-7-chlorobenzo[b]thiophene and 3-methyl bromide-7-chlorobenzo[b]thiophene.

The enantiomers of sertaconazole in the form of a free base may be converted into pharmaceutically acceptable salts are known in this field means. Preferably receive Mononitrate by treatment with nitric acid.

The stage of obtaining enantiomers of sertaconazole presented in the following diagram.

In addition, the present invention relates to farm celticism songs including (R)-(-)-sertaconazole and/or its salt, and (R)-(-)-sertaconazole and/or its salts for the treatment of infections caused by fungi and yeasts, in humans and animals, and diseases of agricultural crops caused by such microorganisms.

Compounds of the present invention, optionally mixed with pharmaceutically acceptable carriers, you can enter the human or animal by mouth in the form of tablets, capsules, coated tablets, syrups, solutions, powders, granules, emulsions, gels for oral administration, pastes for oral administration, buccopharyngeal solutions, buccopharyngeal suspensions, buccopharyngeal gels, buccopharyngeal pastes and the like; by injection, rectally way and vaginally-intrauterine method in a form similar to the egg, vaginal tablet, vaginal capsules, treatment of vaginal swab, ointment, cream, gel, foam, solution, emulsions, suspensions, pessary, lotion, etc. in a daily dose of from 50 to 400 mg; and local way in the form of a cream, lotion, paste, suspension, ointment, emulsion, solution, foam, shampoo, powder, gel, etc. in a concentration in the range from 0.05 to 3%.

Compounds of the present invention can optionally be mixed with a diluent or carrier and used for disease control in weste the economic crops by application to the soil by watering, sputtering, spraying, dusting, or in the form of powder, cream, paste, etc. at the rate of deposition of 0.05 to 10 kg per 1 hectare of soil.

The implementation of the invention

The following examples are provided to illustrate methods for obtaining enantiomers of sertaconazole containing pharmaceutical compounds and their biological activity against various microorganisms.

Example 1: R-(-)-1-(2,4-dichlorophenyl)-2-imidazol-1-retinol

In odnogolosy flask of 50 ml volume, equipped with a dropping funnel, a cooling bath, a magnetic stirrer and container with nitrogen, mixed 3,14 g (9.8 mmol, 2.5 EQ.) chloride (-)-DIP and 9 ml of anhydrous ethyl ether (molecular sieves 4 Å). To the mixture dropwise at room temperature under nitrogen atmosphere add a solution of 1 g (to 3.92 mmol, 1 EQ.) 1-(2,4-dichlorophenyl)-2-imidazol-1-ratanana in 10 ml of anhydrous tetrahydrofuran (molecular sieves 4 Å). The mixture is stirred for 24 h at room temperature in a nitrogen atmosphere. To this mixture, 0.4 ml of methanol, stirred for 10 min and the solvents removed by evaporation under reduced pressure.

To the obtained crude product add 10 ml of n-hexane and 10 ml of water. The mixture is acidified by the addition of 1.6 ml of 6 M hydrochloric acid. The two phases are separated and the organic layer removed. The aqueous phase is neutralized 3 M NaOH to pH 10-11 in the presence of 10 ml this is new ether. The two phases are separated and the organic layer washed with 10 ml of ethyl ether. Two ether layer is dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure, thus obtain 1.27 g of the crude product, which crystallized from a mixture of 5 ml of a mixture of ethanol/water, 1:1 vol./about., thus obtain 0.8 g (yield 80%) of R-(-)-1-(2,4-dichlorophenyl)-2-imidazol-1-retinol. The results of the analysis:

DSC: peak at 107,4°

The IR spectrum corresponds to the specified structure

1H13C-NMR (DMSO) spectrum corresponds to the specified structure

[α]D20(C=1%, Meon)=-80

Example 2: R-(-)-1-(2,4-Dichlorophenyl)-2-imidazol-1-retinol

A solution of 5 g of 1-(2,4-dichlorophenyl)-2-imidazol-1-retinol in a mixture of acetone/methanol (25 ml/20 ml) is added slowly to D-tartaric acid (3,21 g), dissolved in a mixture of acetone/methanol (25 ml 10 ml) at room temperature. After adding the reagent, the reaction mixture is stirred for another 30 min at comentou temperature. The resulting solid is filtered off and recrystallized from methanol. The output is 1.85 g (37%), enantiomer purity of R-isomer >98%.

Example 3: (R)-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazol

In a three-neck flask with a volume of 100 ml, equipped with a reflux condenser, immersion thermometer, dropping funnel, cooling bath and the container with nitrogen, mix 10 ml of dry N,N-dimethylformamide (molecular sieves 4 Å) and 1.27 g (11.3 mmol, 1.03 EQ.) tert-butoxide potassium. To the resulting mixture, cooled in a water bath, is added dropwise a solution of 2.83 g (11 mmol) of (R)-(-)-1-(2,4-dichlorophenyl)-2-imidazol-1-retinol in 15 ml of dry N,N-dimethylformamide. After complete addition, the mixture is stirred for 45 min and to the solution was added with 2.93 g in (11.2 mmol, of 1.02 EQ.) 3-methyl bromide-7-chlorobenzo[b]thiophene in 7 ml of dry N,N-dimethylformamide. The reaction mixture was stirred for 4 h at room temperature. The solvent is removed by distillation under reduced pressure and the residue treated with 50 ml of methylene chloride. The resulting solution is washed with 2 times 30 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure, you get to 4.62 g of the crude product. The crude product was then purified column chromatography on silica gel using as eluent a gradient methylene chloride/methanol. The resulting resin (2.0 g) is crystallized from ethyl ether (10 ml). The solid is filtered off and dried, thus obtain 1.22 g (yield of 25.1%) of (R)-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole.

The results of the analysis:

DSC: peak at 74,5°

The IR spectrum corresponds to the specified structure

1H13With the Mr (DMSO) spectrum corresponds to the specified structure

[α]D20(C=1%, Meon)=-61,0

Example 4: (S)-(+)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazol

In a three-neck flask with a volume of 100 ml, equipped with a reflux condenser, immersion thermometer, dropping funnel, cooling bath and the container with nitrogen, mix 16 ml of dry N,N-dimethylformamide (molecular sieves 4 Å) and 2,04 g (18,43 mmol, of 1.05 equiv.) tert-butoxide potassium. To the resulting mixture, cooled in a water bath, is added dropwise a solution of 4.44 g (17,2 mmol) of (S)-(+)-1-(2,4-dichlorophenyl)-2-imidazol-1-retinol in 25 ml of dry N,N-dimethylformamide. After complete addition, the mixture is stirred for 45 min and to the solution add 4.61 in (17,62 mmol, of 1.02 EQ.) 3-methyl bromide-7-chlorobenzo[b]thiophene in 13 ml of dry N,N-dimethylformamide. The reaction mixture was stirred for 4 h at room temperature. The solvent is removed by distillation under reduced pressure and the residue is treated with 80 ml methylene chloride. The resulting solution is washed with 2 times 50 ml of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure, thus receive 7.30 g of the crude product. The crude product was then purified column chromatography on silica gel using as eluent a gradient methylene chloride/methanol. The resulting resin (3,78 g) is crystallized from ethyl is about ether (18 ml). The solid is filtered off and dried, thus receive 2,61 g (yield of 34.5%) of (S)-(+)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole.

The results of the analysis:

DSC: peak at of 83.4°

The IR spectrum corresponds to the specified structure

1H13C-NMR (DMSO) spectrum corresponds to the specified structure

[α]D20(C=1%, Meon)=+69

Example 5: Mononitrate (R)-(-)-sertaconazole (Mononitrate (R)-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole)

880 mg(for 2.01 mmol)of(R)-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole are dissolved in 5 ml of 96% ethanol. To the solution add 1 ml of water and heated at a temperature of 35-37°C. To the resulting solution was added to 0.23 ml of 60% nitric acid (3 mmol, 1.5 EQ.). Then add 3 ml of water and cooled first to room temperature, and then with a 10°C for 1 h resulting solid substance is filtered off, washed 2 times with 4 ml of water and dried in vacuum for 24 h, thus receive 0.9 g (yield 89%) of Mononitrate (R)-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole.

The results of the analysis:

DSC: peak at 116,87°

The IR spectrum corresponds to the specified structure

1H13C-NMR (DMSO) spectrum corresponds to the specified structure

[α]D20(C=1%, Meon)=-85,00

Example 6: Mononitrate (R)-(-)-sertaconazole (Mononitrate R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole

In a flask with a volume of 500 ml, equipped with a mechanical stirrer, download 15,72 g of R-(-)-1-(2,4-dichlorophenyl)-2-imidazol-1-retinol, 45 ml of toluene, of 1.05 g of tetrabutylammonium hydrosulfate and 24.5 g 18 N. aqueous NaOH. The mixture is heated at 35-40°and this temperature is maintained for another 15 minutes Then add a solution of 3-methyl bromide-7-chlorobenzo[b]thiophene in 376 ml of toluene for 30 minutes In the reaction mixture keep the temperature from 37 to 40°C for 2.5 h and then add water. The organic layer is washed with water. After concentration under reduced pressure the crude product is dissolved in 150 ml of absolute ethanol. Then slowly add a mixture of 9.1 g of 60% HNO3and 130 ml of water and after addition of reagents, the reaction mixture was cooled to 0°C. the Obtained solid is filtered off, recrystallized from a mixture of acetone/ethanol and dried. The output of 24.5 g (80%).

Example 7: Mononitrate (S)-(+)-sertaconazole (Mononitrate (S)-(+)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole)

2.35 mg (5.37 mmol)of(S)-(+)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole are dissolved in 17 ml of 96% ethanol. To the solution add 3 ml of water and heated at a temperature of 35-40�B0; C. To the resulting solution was added and 0.61 ml of 60% nitric acid (of 8.06 mmol, 1.5 EQ.). Then add 13 ml of water and cooled at room temperature, and then with a 10°C for 1 h Obtained solid is filtered off, washed with 2 times 10 ml of water and dried in vacuum for 24 h, thus receive 2.65 g (yield of 98.5%) Mononitrate (S)-(+)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole.

The results of the analysis:

DSC: peak at 168,91°

The IR spectrum corresponds to the specified structure

1H13C-NMR (DMSO) spectrum corresponds to the specified structure

[α]D20(C=1%, Meon)=+89,00

Example 8: a part of the 1% cream

Composition per 100 g
Mononitrate R-(-)-sertaconazole1,00 g
Mono - and diglycerides of palmitic and stearic acids6,00 g
Cetostearyl alcohol containing 20 mol of ethylene oxide1,00 g
Decroly ester of oleic acid5,00 g
Monoethanolamine undecylenate acid2,00 g
Carbomer1,00 g
Triethanolamine0,60 g
Methylparaben0.15 g
About Elparan 0.05 g
Distilled water to volume100,00 g

Example 9: the composition of the gel 1%

Composition per 100 g
Mononitrate R-(-)-sertaconazole1,00 g
Propylene glycol10,00 g
Carbomer1,00 g
Tween-200.10 g
Phenoxyethanol0.35 g
The disodium salt of EDTU0.15 g
Citric acid0.25 g
1 N. sodium hydroxide1.50 g
Triethanolamine1.55 g
Distilled water to volume100,00 g

Example 10: Biological data

The minimum inhibitory concentration (MIC) was determined using a modified method of microrasbora M27-As recommended by the National Committee for clinical laboratory standards, in the medium RPMI-1640 (Sigma)supplemented with glucose to a concentration of 2% and brought to pH 7.0 using 0,165 M buffer solution containing morpholine-propanesulfonic acid (MOPS). From initial solutions of the compounds to prepare serial twofold dilution in modified medium RPMI-1640. In the guises MICK determine the minimum concentration of a medicinal product, in which there is inhibition of growth by 50% compared with the growth control organism. Microbiological activity of R-(-)-sertaconazole compared with S-(+)-enantiomer, which is much less active and racemic-sertaconazole presented as geometric mean values in the table. The number of strains used in the experiments is shown in parentheses next to the name of each organism.

MIC (μg/ml) nitrate sertaconazole and its enantiomers
The microorganismR-(-)-enantiomerThe racemateS-(+)enantiomer
Candida spp (42)0,1250,2563,217
Dermatophytes (17)0,040,080,17
Filamentous fungi (11)1,763,1116
Malassezia spp (11)0,641,3710,96

1. R-(-)-1-[2-(7-Chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole of the formula (I)

or its pharmaceutically acceptable salt.

2. Mononitrate R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole.

3. How is Holocene compound according to claim 1 or 2, characterized in that conduct the interaction of R-(-)-1-(2,4-dichlorophenyl)-2-imidazol-1-retinol formula ((R)-(-)-(III)

with 3-halogenmethyl-7-chlorobenzo[b]thiophene of formula (IV)

where X is a halogen, and optionally processes the received R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole salt-forming acid.

4. The method according to claim 3, wherein X is chlorine or bromine.

5. The method according to claim 3 or 4, characterized in that the connection is Mononitrate R-(-)-1 -[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichloro-phenyl)ethyl]-1H-imidazole, and the salt-forming acid is nitric acid.

6. The method according to claim 3 or 4, characterized in that R-(-)-1-(2,4-dichlorophenyl)-2-imidazol-1-retinol formula ((R)-(-)-III) are obtained by enantioselective recovery 1-(2,4-dichlorophenyl)-2-imidazol-1-ratanana using (-)-β-chlorodiisopinocampheylborane-borane.

7. The method according to claim 5, characterized in that R-(-)-1-(2,4-dichlorophenyl)-2-imidazol-1-retinol formula ((R)-(-)-III) are obtained by enantioselective recovery 1-(2,4-dichlorophenyl)-2-imidazol-1-ratanana using (-)-β-chlorodiisopinocampheylborane.

8. The composition having antifungal activity, containing R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichloro-f the Nile)ethyl]-1H-imidazole or its salt.

9. The composition of claim 8 in which the salt is specified Mononitrate.

10. Composition according to any one of claim 8 or 9, which is a pharmaceutical composition.

11. Composition according to any one of claim 8 or 9, which is an agricultural composition.

12. The use of R-(-)-1-[2-(7-chlorobenzo[b]thiophene-3-ylethoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole or its salt as an active ingredient-containing composition.

13. The application indicated in paragraph 12, in which salt is specified Mononitrate.

14. The use according to any one of item 12 or 13, in which this composition is used for treating fungal infections in humans or animals.

15. The use according to any one of item 12 or 13, in which this composition is used for diseases of agricultural crops.



 

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FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to new compounds - C7-ester-substituted taxanes of the general structural formula:

wherein R2 represents benzoyloxy-group; R7 represents R7aCOO-; R10 represents hydroxy-group; X3 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among oxygen (O), nitrogen (N) and sulfur (S) atoms; X5 represents -COX10 wherein X10 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, phenyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among O, N and S; or it (X5) represents -COOX10 wherein X10 represents (C1-C8)-alkyl or (C2-C8)-alkenyl; R7a represents (C1-C20)-alkyl or (C2-C20)-alkenyl; Ac represents acetyl group. These compounds possess an anti-tumor activity. Also, invention relates to a method for inhibition of tumor growth in mammals and to a pharmaceutical composition based on synthesized compounds. Invention provides preparing new derivatives of taxanes possessing the enhanced anti-tumor activity and reduced toxicity as compared with taxol and taxoter.

EFFECT: improved and valuable medicinal properties of compounds.

39 cl, 4 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: veterinary microbiology, mycology, agriculture.

SUBSTANCE: vaccine comprises antigen and adjuvant in the ratio = 10:1. As antigen vaccine comprises complex of cytoplasmic fraction and endotoxin from cellular wall of fungus strain Mucor racemosus N 195 with spore activity (5 x 105)-(6 x 105) in 1 cm3 and agglomeration index of leukocytes 6-15%. Vaccine is effective, safety and possesses high immunogenicity.

EFFECT: valuable properties of vaccine.

1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves cleaning lesion focus from mycotic masses and then treating it with aqueous Tatar motherwort extraction given in concentration of 0.96-3.84 mcg/ml enclosed into 150-30 nm large egg lecithin liposomes.

EFFECT: enhanced effectiveness of treatment; reduced risk of adverse side effects.

FIELD: medicine, otorhinolaryngology.

SUBSTANCE: the present innovation deals with treating mycotic diseases of ears, particularly external otomycosis, otitis mycotica media and otomycosis of post-operational cavity. For this purpose, it is necessary to treat one's ear, then one should apply fir spring coniferous needles or branches and common salt at the ratio of (g) 8:1 - 12:1/1000 ml 70%-ethanol. The present solution should be supplemented with liposomes of egg lecithin at the quantity of 100 mg/ml at the size of 200-250 nm. The present method enables to decrease side effects and toxicity due to applying a medicinal preparation that contains plant components.

EFFECT: higher efficiency of therapy.

1 cl

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):

or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:

wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a ketoconazole-base antifungal pharmaceutical composition. The composition is prepared as a solid medicinal formulation. The composition comprises the following components, wt.-%: ketoconazole, 50.5-75.0; lactose, 1.0-12.0; starch, 5.0-25.0; polyvinylpyrrolidone, 2.0-12.0; stearic acid or calcium, magnesium or zinc stearate or mixture of indicated compounds, 0.2-1.2; aerosil and/or talc, 0.5-10.0. The novel antifungal composition comprises ketoconazole in the amount 50 wt.-%, not less, and it satisfies Pharmacopoeia requirements, stable in storage for 2 years, not less, and shows high therapeutic activity.

EFFECT: improved and valuable medicinal and pharmaceutical properties of composition.

3 cl, 2 tbl, 6 ex

FIELD: urology.

SUBSTANCE: treatment consists in administration of alpha-1-adrenoblocker. Therapy is continued within 4-8 weeks in effective dose. Method leads to aggravation of symptoms of disease during the treatment followed by stopping manifestations of disease after cessation of giving preparation due to elimination of disbalance in functioning of current-coordinated detrusor-cervix-urethra system.

EFFECT: expanded possibilities in treatment of stress-caused urological diseases.

7 cl, 2 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with antimycotic composition that includes either antibody or antigen-binding fragment being specific to the epitope of mycotic protein of thermal shock, and antimycotic agent for treating mycotic infections, where fungus is resistant to the agent mentioned per se. Moreover, a kit for treating mycotic diseases is also suggested.

EFFECT: increased number of antimycotic means.

11 cl, 23 tbl

FIELD: medicine, dermatology.

SUBSTANCE: invention proposes an anti-infectious preparation comprising the combination of active substances with topical and systemic antifungal agents and a water-insoluble film-forming agent. The systemic antifungal agent is taken among the group including intraconazole, terbinafine and fluconazole or their salts. The topical antifungal agent is taken among the group including ciclopirox, 6-(2,4,4-trimethylpentyl)-1-hydroxy-4-methyl-2(1H)-pyridone, amorolfine and butenafine or their salts. The preparation is used as lacquer for nails in therapy of onychomycosis. The lacquer preparation provides high concentration of systemic antifungal agents in nails after its topical applying. The significant advantage of the preparation involves short time in treatment of anychomycosis.

EFFECT: enhanced effectiveness and valuable medicinal properties of preparation.

6 cl, 6 ex

FIELD: medicine, veterinary science.

SUBSTANCE: a new group of compounds, such as: 1) 1.3-benzodixole-5-β-nitroethylene

, 2) 1.3-benzodioxole-5-β-nitropropylene

, 3)benzimidazole-5-β-nitropropylene

, 4) 2-methylbenzimidazole-5-β-nitroethylene

, 5) benzoxazole-5-β-nitroethylene

, 6) 2-methylbenzoxazole-5-β-nitropropylene

has been suggested to protect against the agents of bacterial, protozoan and fungoid nature. Compounds are being the derivatives of heteronitroalkenes (dioxoles, oxazoles, imidazoles) with below-mentioned structural formulas being efficient to gram-positive bacteria and gram-negative aerobes, fungi of Candida, Trichophyton and other types, trichomonads. They could be applied at treating wound infections, fungoid lesions, septic states, pneumonia, trachoma, ornithosis, salmonellosis.

EFFECT: higher efficiency of protection.

5 cl, 5 tbl

FIELD: medicine, dermatology, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to an antifungal gel pharmaceutical composition based on ketoconazole and clotrimazole that are derivatives of imidazole. The composition comprises ketoconazole or clotrimazole as an active component, polyethylene glycol-400 (PEG-400) as a solvent, carboxyvinyl polymer as a gel-forming agent, polyethylene glycol as a gel stabilizing agent, organic amine or inorganic bas as a regulator of pH and water taken in the definite ratio of components. The composition is prepared by dissolving active component in PEG-400, dispersing carboxyvinyl polymer in water, successive addition to dispersion propylene glycol as a stabilizing agent and regulator of pH and combination of prepared solution and gel followed by stirring the mixture up to preparing the gel composition with pH 5-7. Invention provides preparing antifungal composition with reduced adverse effect.

EFFECT: improved preparing method, valuable medicinal properties of composition.

2 cl, 1 tbl, 11 ex

FIELD: medicine, cardiology.

SUBSTANCE: invention proposes an agent for correction of abdominal complications in acute period in myocardium infarction. Proposed agent represents ondansetron or domperidone. Agent reduces frequency of hyperemia occurring, improved indices of intestine contractions, promotes to declining lethality in acute period in myocardium infarction.

EFFECT: improved and valuable medicinal properties of agent.

4 tbl, 6 dwg

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